The proposal deals with biotransformation and disposition studies of cocaine in animals using gas chromatography-mass spectrometry. In this study site specific radio labeled and stable isotope labeled cocaine and its biologically active metabolite, norcocaine will be synthesized. Animals would be given equimolar mixture of cocaine d0-cocaine-d6 along with cocaine-14C and cocaine-3H. The 14C/3H ratio, incorporated in the dose, would greatly simplify the separation of metabolites while the d0-d6 doublet would facilitate the mass spectrometric identification of metabolites. The methodology, already developed for the quantitation of cocaine and its pharmacologically active metabolite will be used to delineate cocaine pharmacokinetics in plasma, urine and whole brain. Pharmacokinetic studies in chronic conditions would be undertaken. This would involve administration of a single pulse dose or cocaine-d3 to animals maintained on daily cocaine dosage for two weeks. Cocaine, cocaine-d3 as well as norcocaine and norcocaine-d3 would be measured in plasma, urine and whole brain at appropriate time intervals using cocaine-d8 and norcocaine-d8 as internal standards. This study would enable us to estimate pharmacokinetic parameters in acute and chronic conditions. Metabolic pathways, once defined, would lead to the synthesis of specific enzyme inhibitors and/or anti-metabolite(s) and would be a major step toward cocaine detoxification.